In the United States, roughly 10% of the total population is exposed to hazardous levels of noise in the workplace on a daily basis (National Institute for Occupational Safety and Health, //www.cdc.gov/NIOSH/). The damage sustained by the cochlea from chronic impulse noise (subsonic) or sudden blast exposure (supersonic) leads to permanent and debilitating hearing loss and tinnitus. Pre-exposure diagnostics and the development of targeted therapies are sorely needed. Estimates from human twin studies suggest heritability for noise induced hearing loss (NIHL) of approximately 36% and although several candidate gene association studies for NIHL have been conducted, however;each lacks power due to the difficulties in finding well-characterized cohorts of sufficient size. The similarities, both anatomically and genetically, between the mouse and human inner ears, coupled with the known strain variation in phenotypes, makes the mouse an ideal model for gene discovery. In this application we propose two specific aims to identify genes and pathways that confer susceptibility to NIHL. Our overriding hypothesis is that among inbred strains of mice there are genetic variants relevant to the molecular mechanisms and pathways underlying susceptibility to NIHL. The primary aim of this study is to comprehensively define loci that contribute to this variation using Genome-Tagged Mice (Aims 1a), to perform high-resolution mapping of the same and additional loci using a Hybrid Mouse Diversity Panel (Aim 1b) and to integrate this with cochlear transcript levels to model biologic networks and identify causal variants (Aims 1c and 2). The findings from the experiments described in this application will form the basis for hypotheses to be tested in human populations. PUBLIC HEALTH RELEVANCE: There is evidence in both mice and humans that there is a heritable component to noise-induced hearing loss (NIHL). The similarities, both anatomically and genetically, between the mouse and human inner ears, coupled with the known strain variation in phenotypes, makes the mouse an ideal model the genetic analysis of strain variation using high-resolution mapping strategies. The primary aim of this study is to comprehensively define loci that contribute to this variation using novel and straight-forward methodologies. The findings from the experiments described in this application will form the basis for hypotheses to be tested in human populations.